UT Health San Antonio, TX, USA San Antonio, Texas, United States of America
Background: Tuberous Sclerosis Complex (TSC) is linked to the development of several tumors including kidney angiomyolipomas.
Methods: Kidney, skin and intestine tumors from TSC patients, as well as angiomyolipoma human cells and TSC2-deficient mouse cells showed significant increase in miR21 levels compared to normal tissues and normal renal cells. We generated a new double knockout mouse model of TSC2+/-/miR21-/- to examine whether eliminating miR21 will prevent kidney tumor progression.
Results: We observed a significant increase in miR21 levels in the kidney of TSC2+/- mice compared to WT mice at age 8 -10 months, however, such increase was abolished in the kidney of the new mouse model TSC2+/-/miR21-/-. Further, the TSC2+/-/miR21-/- mice showed a significant decrease in kidney tumor number and tumor volume compared to TSC2+/- mice. RNA sequence data of kidney tissues from TSC2+/-/miR21-/- mice showed several differentially expressed genes compared to miR21-/-, TSC+/- and WT mice. Further, we identified Guanine nucleotide‐binding protein subunit gamma‐12 (Gng12) as a new target gene of TSC2 highly expressed in the kidney of TSC2+/- mice, angiomyolipoma cells and in several tumors from TSC patients.
Conclusions: We provided for the first time in vivo evidence that losing miR21 suppresses kidney tumor progression in the new mouse model (TSC2+/-/miR21-/-). These data suggest that silencing miR21 is a potential therapeutic approach for treatment/prevention tumorigenesis in TSC patients. In addition, higher expression of Gng1 in renal cells, kidney mice and in human tissues deficient in tuberin suggests a novel oncogenic role of Gng12 as a new gene involves in kidney tumor progression.